Drug-eluting medical implants

ABSTRACT

Disclosed are self-expanding medical implants for placement within a lumen of a patient. The implants comprise a woven or non-woven structure having a substantially tubular configuration, and are designed to be low-profile such that they are deliverable with a small diameter catheter. The implants have a high recoverability and desired mechanical properties.

This application is a continuation-in-part of, and claims the benefit ofand priority to U.S. patent application Ser. No. 13/891,574, filed May10, 2013, U.S. patent application Ser. No. 13/863,632, filed Apr. 16,2013, which claims the benefit of priority to U.S. Provisional PatentApplication Nos. 61/624,607, filed Apr. 16, 2012; U.S. patentapplication Ser. No. 13/766,294, filed Feb. 13, 2013, U.S. patentapplication Ser. No. 13/370,025, filed Feb. 9, 2012; U.S. patentapplication Ser. No. 13/253,720, filed Oct. 5, 2011; U.S. patentapplication Ser. No. 13/183,104, filed Jul. 14, 2011; and U.S. patentapplication Ser. No. 13/032,281, filed Feb. 22, 2011; all of which arecontinuations-in-part of, and claim the benefit of and priority in U.S.patent application Ser. No. 12/783,261, filed May 19, 2010; which claimsthe benefit of and priority to 61/179,834, filed May 20, 2009;61/227,308, filed Jul. 21, 2009; and 61/251,984, filed Oct. 15, 2009,each of which is incorporated herein in their entireties for allpurposes.

FIELD OF THE INVENTION

The present invention relates to medical implants, and morespecifically, to drug eluting medical implants that are intended forplacement within a lumen or cavity of a patient.

BACKGROUND

A variety of medical conditions are treatable by the implantation oftubular devices into natural body lumens. For example, it is commonplaceto implant metallic stents into the coronary arteries of patients withheart disease following balloon angioplasty to minimize the risk thatthe arteries will undergo restenosis. Recently, commercial stents haveincluded drug-eluting polymer coating that are designed to furtherdecrease the risk of restenosis. Other examples of conventional tubularmedical implants include woven grafts and stent grafts that are used tospan vascular aneurysms, polymeric tubes and catheters that are used tobypass strictures in the ureter and urethra, and stents that are used inthe peripheral vasculature, prostate, sinus and esophagus. It should berecognized that the size of the devices of the present invention willdepend upon their clinical application. For example, stents for theesophagus and other large bodily lumens may be as large as 30 mm or 40mm in diameter or larger.

Despite the evolution of metallic stents, they continue to havelimitations such as the possibility of causing thrombosis, restenosis,and vascular remodeling. While the use of biodegradable and biostablepolymeric materials for stents and other implantable devices has beenproposed to eliminate the possible long-term effects of permanentimplants, the use of such materials has been hindered be relatively poorexpandability and mechanical properties. For example, the expansioncharacteristics and radial strength of prototype stents made frombiodegradable and biostable polymeric materials has been significantlylower than that of metallic stents. This is particularly the case wheresuch stents are low profile and make use of small diameter fibers orthin walled struts that comprise the stent body. Furthermore, thedegradation rate and the manner in which such devices degrade in thebody have been difficult to control. Finally, where such devices areused as a drug delivery vehicle, the drug elution rate has beendifficult to reproducibly characterize.

There is therefore a need for low-profile, self-expanding implantabletubular devices that have sufficient expansion characteristics, strengthand other mechanical and drug release properties that are necessary toeffectively treat the medical conditions for which they are used. Thereis also generally a need to provide such devices that include the lowestpossible dose of drug that is able to provide clinically effectiveresults.

SUMMARY

In one aspect, the present invention includes an implantable medicaldevice for placement within a lumen or cavity of a patient. In anotheraspect, the present invention includes a method of loading the medicaldevice into a delivery catheter just prior to being implanted into apatient. In another aspect, the present invention includes a method oftreating a patient by delivering the medical device to a target locationwithin the patient. In yet another aspect, the present inventionincludes a kit that comprises the implantable medical device.

The devices of the present invention are generally tubular structuresmade from polymeric or metallic strands as described herein. In certainembodiments, the devices comprise tubular structures comprisingpolymeric strands, and further comprising a therapeutic agent, such aspaclitaxel. The amount of therapeutic agent is within the range of about0.002 to about 0.175 micrograms per square millimeter of the surfacearea of the tubular structures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an implantable braided medical device, inaccordance with an embodiment of the present invention.

FIG. 2 is a side view of an implantable unitary framework medicaldevice, in accordance with an embodiment of the present invention.

FIG. 3 is a cross-sectional view of a strand of an implantable medicaldevice in accordance with an embodiment of the present invention thatincludes a support coating.

FIG. 4 is a side view of a strand of an implantable medical device inaccordance with an embodiment of the present invention that includesdiscrete areas of therapeutic agent thereon.

FIG. 5 is a cross-sectional view of a strand of an implantable medicaldevice in accordance with an embodiment of the present invention thatincludes a therapeutic agent coating and a topcoat.

FIG. 6 shows the cumulative release over time of paclitaxel from thedrug eluting implants of the present invention containing 12, 8 and 4micrograms of paclitaxel.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides for medical implants that have expansioncharacteristics and mechanical properties that render them suitable fora broad range of applications involving placement within bodily lumensor cavities. As used herein, “device,” “implant,” “stent,” and“scaffold” are used synonymously. Also as used herein, “self-expanding”is intended to include devices that are crimped to a reducedconfiguration for delivery into a bodily lumen or cavity, and thereaftertend to expand to a larger suitable configuration once released from thedelivery configuration, either without the aid of any additionalexpansion devices or with the partial aid of balloon-assisted orsimilarly-assisted expansion. When compared with conventionalself-expanding medical implants, the implants of the present inventionrecover to an exceptionally high percentage of their manufactureddiameter after being crimped and held in a small diameter for deliveryinto a bodily lumen. Moreover, when compared with conventionalself-expanding implants and particularly polymeric implants, theimplants of the present invention are characterized by much improvedstrength and other desired mechanical properties. As used herein,“strength” is used to mean the resistance of the medical implants of thepresent invention to deformation by radial forces. Examples of strengthmeasurements, as used to characterize the medical implants of thepresent invention, include radial resistive force and chronic outwardforce, as further defined herein. Also, when compared with conventionaldrug eluting stents, the implants of the present invention comprise arelatively small quantity of therapeutic agent while are nonethelessable to provide favorable preclinical results. A low quantity oftherapeutic agent is desirable for numerous reasons, such as to reducethe manufacturing cost and to minimize the possibility of producingunintended effects in tissues adjacent to the target tissue to betreated.

In one embodiment shown in FIG. 1, the implant 100 preferably comprisesat least one strand woven together to form a substantially tubularconfiguration having a longitudinal dimension 130, a radial dimension131, and first and second ends 132, 133 along the longitudinaldimension. As used herein, “strand,” “fiber,” “strut” are usedsynonymously to mean the elements that define the implant configuration.As used herein, “woven” is used synonymously with “braided.” Forexample, the tubular configuration may be woven to form a tubularstructure comprising two sets of strands 110 and 120, with each setextending in an opposed helix configuration along the longitudinaldimension of the implant. The sets of strands 110 and 120 cross eachother at a braid angle 140, which may be constant or may change alongthe longitudinal dimension of the implant. Preferably, there are betweenabout 16 and about 96 strands used in the implants of the presentinvention, more preferably between about 16 and about 32 strands, andthe braid angle 140 is within the range of about 90 degrees to about 135degrees throughout the implant. The strands are woven together usingmethods known in the art, using known weave patterns such as Regularpattern “1 wire, 2-over/2-under”, Diamond half load pattern “1 wire,1-over/1-under”, or Diamond pattern “2 wire, 1-over/1-under”.

The strands are preferably made from at least one biodegradable materialthat is preferably fully absorbed within about two years of placementwithin a patient, and more preferable within about one year of placementwithin a patient. In some embodiments, the strands are fully absorbedwithin about six or fewer months of placement within a patient. Thefirst and second strand sets 110, 120 may be made from the same ordifferent biodegradable polymer. In other embodiments, the first and/orsecond strand sets 110, 120 may be made from biodegradable metallicmaterials such as magnesium or zinc, or from biostable metallicmaterials such as stainless steel, chromium-cobalt alloys, or othersuitable biocompatible materials. Non-limiting examples of biodegradablepolymers that are useful in the at least one strand of the presentinvention include poly lactic acid (PLA), poly glycolic acid (PGA), polytrimethylene carbonate (PTMC), poly caprolactone (PCL), poly dioxanone(PDO), and copolymers thereof. Preferred polymers are poly(lactic acidco-glycolic acid) (PLGA) having a weight percentage of up to about 20%lactic acid, or greater than about 75% lactic acid (preferably PLGA88:12 (wt:wt)), with the former being stronger but degrading in the bodyfaster. The composition of PLGA polymers within these ranges may beoptimized to meet the mechanical property and degradation requirementsof the specific application for which the implant is used. For desiredexpansion and mechanical property characteristics, the materials usedfor the strands preferably have an elastic modulus within the range ofabout 1 to about 10 GPa, and more preferably within the range of about6-10 GPa.

The strands used in the implant 100 preferably have a cross-sectionaldiameter in the range of from about 0.003 inches to about 0.007 inches,with embodiments including 0.003, 0.004, 0.005, 0.006 and 0.007 inches,and intervals therebetween. Where multiple strands are used, they may beof substantially equal diameters within this range, or first strand set110 may be of a different general diameter than second strand set 120.In some embodiments, multiple strand sets are used with differentdiameters such that the implant includes three, four or more differentdiameter strands. In either event, the diameters of strands are chosenso as to render the implant 100 preferably deliverable from a 10 Frenchdelivery catheter (i.e., 3.3 mm diameter) or smaller, and morepreferably from a 7 French delivery catheter (i.e., 2.3 mm diameter) orsmaller. The ability to place the implant of the present invention intosmall diameter delivery catheters allows for its implantation into smalldiameter bodily lumens and cavities, such as those found in thevascular, biliary, uro-genital, iliac, and tracheal-bronchial anatomy.Exemplary vascular applications include coronary as well as peripheralvascular placement, such as in the superficial femoral artery (SFA). Itshould be appreciated, however, that the implants of the presentinvention are equally applicable to implantation into larger bodilylumens, such as those found in the gastrointestinal tract, forapplications such as esophageal scaffolds.

In another embodiment of the present invention, the implant is anon-woven, self-expanding structure, such as a unitary polymericframework. As shown in FIG. 2, the non-woven implant 100 is preferablycharacterized by a regular, repeating pattern such as a latticestructure. The use of a unitary framework may provide a reduced profilewhen compared to the use of woven strands, which yield a minimum profilethat is the sum of the widths of overlapping strands. In addition, aunitary framework eliminates the possible change in length of theimplant associated with crimping and subsequent expansion, known asforeshortening, which is common in braided stents. When the implant 100is a unitary framework, it is fabricated using any suitable technique,such as by laser cutting a pattern into a solid polymer tube. In apreferred embodiment, when the implant 100 is a unitary framework, it isformed by laser cutting and includes a wall thickness of between about75 and about 100 microns. It should be recognized that while the presentinvention is described primarily with reference to woven strandconfiguration, aspects of the present invention are equally applicableto non-woven, self-expanding structures unless necessarily or expresslylimited to woven configurations.

Certain embodiments of the present invention make use of 16, 24 or 32strands. These embodiments are characterized by surface areas as setforth in Table I.

TABLE I Surface areas of certain embodiments of the present invention.Surface area (square millimeters per millimeter of implant length) No.of strands 0.003″ strands 0.004″ strands 0.005″ strands 0.006″ strands0.007″ strands 32 22.7-24.4 30.3-31.6 37.9-39.0 45.4-46.3 53.1-53.8 2417.1-18.3 22.7-23.7 28.5-29.2 34.1-34.7 39.8-40.4 16 11.4-12.2 15.1-15.819.0-19.5 22.7-23.2 26.5-26.9

As can be seen from Table I, certain embodiments of the presentinvention have surface areas within the range of about 11.4 squaremillimeters per every millimeter of implant length (in the case ofcertain embodiments having 16 strands of 0.003″ cross-sectionaldiameter) to about 53.8 square millimeters per millimeter of implantlength (in the case of certain embodiments having 32 strands of 0.007″cross-sectional diameter). It should be noted that the embodiments ofthe present invention included in Table I generally have a braid angleof about 127 degrees, and that varying braid angle and other scaffoldattributes may influence surface area.

There are a variety of strengthening means that are useful in thepresent invention to help provide the expansion and mechanicalproperties that are needed to render the implant 100 effective for itsintended purpose. In one embodiment, the strengthening means is asupport coating 410 on at least one of the strands of the implant 100.Although referred to herein as a “coating,” the support coating 410 doesnot necessarily coat the entire implant 100, and may not form a discretelayer over the strands or unitary framework of the implant 100; rather,the support coating 410 and underlying strands or unitary framework maybe considered as a composite structure. The support coating 410 is madefrom an elastomeric polymer that, due to its elastic nature whencompressed or elongated, applies a force to implant 100 that acts infavor of radial expansion and axial contraction, thus enhancing radialstrength. The polymer of the support coating 410 is preferablybiodegradable. Alternatively, the support coating 410 is made from ashape memory polymer or a polymer that otherwise contracts upon heatingto body temperature. The inventors have surprisingly found that the useof support coating on the polymeric implants of the present inventioncan result in the recovery of more than 90% of implant diameterpost-crimping, and yield significantly higher radial forces whencompared with uncoated implants or even with self-expanding metallicstents. The support coating 410 may be applied as a conformal coating(as shown in cross-section of an individual strand in FIG. 3, a“conformal” coating as used herein is a coating that generally conformsto the shape of the underlying strand), may be partially applied to oneor more individual strands such that the support coating 410 is appliedto only a portion of the implant along its longitudinal dimension, ormay be applied to only the inner or outer diameter of one or moreindividual strands. Also, the support coating 410 may optionally vary inweight along the length of the implant; for example, the ends of theimplant may be coated with a thicker layer than the mid-section toprovide added support to the ends of the implant. In addition, thesupport coating may accumulate at the crossover points or “nodes” of thewoven device, which has the effect of aiding in diameter recovery andthe achievement of preferred strength characteristics.

Examples of polymer materials used for the support coating 410 includesuitable thermoplastic or thermoset elastomeric materials that yield theelongation, mechanical strength and low permanent deformation propertieswhen combined with the implant strand(s). The inventors have foundexamples of suitable polymers to include certain random copolymers suchas poly(lactic acid-co-caprolactone) (PLCL),poly(glycolide-co-caprolactone) (PGCL), and poly(lacticacid-co-dioxanone) (PLDO), poly(butylene succinate) (PBS),poly(p-dioxanone) (PDO), certain homopolymers such as poly trimethylenecarbonate (PTMC), and copolymers and terpolymers thereof.

In certain embodiments, such polymers are optionally crosslinked with acrosslinker that is bi- or multi-functional, polymeric, or smallmolecule to yield a thermoset polymer having a glass transitiontemperature (Tg) that is preferably lower than body temperature (37°C.), more preferably lower than room temperature (25° C.), and mostpreferably lower than about 1020 C. The thermoset elastomers provide ahigh elongation to break with low permanent deformation under cyclicmechanical testing.

In one preferred embodiment, the polymer material used for the supportcoating 410 is a biodegradable thermoset elastomer synthesized from afour arm PGCL polymer having a weight ratio of approximately 50:50 GA:CLthat is crosslinked with hexamethylene diisocyanate (HDI) to give apolyester with urethane crosslinks. Without wishing to be bound bytheory, the inventors believe that the combination of the elasticsegment (polyester portion) and the interactions (such as hydrogenbonding, allophanate or biuret formation) between the urethane segmentsof such polymers, in addition to a certain crosslinking density, yieldspreferred properties such as a high degree of elastic recovery undercyclic mechanical strain and high overall elasticity.

In other preferred embodiments, the support coating comprises PLCLhaving a weight ration of approximately 50:50 LA:CL. In yet anotherpreferred embodiment, a PLCL 50:50 crosslinked with hexamethylenediisocyanate support coating is applied to a PLGA 88:12 (wt:wt) braidedimplant.

The polymer material used for support coating 410 may be optimized fordesired mechanical properties. For example, the inventors have foundthat the molecular weight of such polymers may be manipulated to enhancecoating performance. As an example, when PLCL 50:50 crosslinked withhexamethylene diisocyanate is used as the support coating of the presentinvention, the inventors have found that a molecular weight (Mn) betweenabout 30 kDa and 120 kDa, preferably from 33 k to 80 k, results in alower modulus of elasticity and a higher strain to fracture, thus makingthe coating better able to adhere to a PLGA braided implant duringdeployment. Similarly, the inventors have found that when PGCL 50:50(wt:wt) crosslinked with hexamethlylene diisocyanate is used as thesupport coating of the present invention, a molecular weight (Mn) from 8kDa to 20 kDa does not yield an appreciable change in properties, butthat a further increase in molecular weight to 50 kDa results in afour-fold increase in the strain at failure of the coating material. Assuch, a preferred range of molecular weight (Mn) for PGCL used in theimplants of the present invention is about 23 kDa to about 100 kDa.Additionally, the inventors have found that the viscosity of the spraycoating solution, the weight percent of crosslinker used in the spraycoating solution, and the temperature and duration of the supportcoating crosslinking process can be optimized to provide preferredcoating morphologies and radial forces.

In the event that the support coating 410 comprises a thermosetelastomer polymer, the crosslink density may be varied to yield desiredmechanical properties. For example, chain terminators may be used inthermoset elastomeric materials such as polyester urethanes to controlcrosslink density. The chemical crosslink density is adjusted by usingsuch chain terminators to control the degree of crosslinking takingplace during the thermoset curing process. The crosslink density of theresultant elastomers depends on the concentration of chain terminatorsincorporated into the elastomeric network. Both small molecular agentsand polymers may react with chain terminators. In some embodiments, HDIis used as a cross-linker, and the prepolymer is provided in a ratio ofbetween 1:1 and 25:1 wt/wt relative to HDI. Any suitable unreactiveorganic solvent may be used in the present invention, includingdichloromethane (DCM), ethyl acetate, acetone, methyl tert-butyl ether,toluene, or 2-methyltetrahydrofuran. Examples of suitable chainterminators in this embodiment include any suitable monofunctionalcompound such as monoisocyanates that contain only one of the functionalgroup R—N═C═O, or monoalcohols that contain only one of the functionalgroup R3—OH. Other examples of suitable chain terminators include smallmolecular agents and polymers that carry one active functional groupthat may react with either isocyanate or hydroxyl groups, such as butnot limited to amines, alcohols, isocyanates, acyl chlorides, andsulfonyl chlorides. The suitable chain terminator is provided in a widerange of amounts (0-20 wt % relative to the prepolymer) to control thecross-linking density. When used with an embodiment of the presentinvention, the solution of polyester, crosslinker, and chain terminatoris dissolved in a solvent and spray coated onto the surface of theimplant 100 and cured to form support coating 410 as a conformalelastomeric coating.

The support coating 410 is coated onto the surface of the implant 100using any suitable method, such as spraying, dipping, electrospraying,rolling and the like. If implant 100 is a woven structure, the supportcoating 410 may be applied to individual strands prior to forming thewoven structure, or to the woven structure after the formation thereof.In this case, owing to surface tension, the coating preferably collectsat intersection points between strands. If implant 100 is a non-wovenstructure, the support coating 410 may be applied, for example, to asolid polymer tube either before or after the removal of material suchas by laser cutting to form a patterned, non-woven structure.

The amount of support coating 410 applied to the implant 100 has beenidentified as one of the factors that contribute to the expansioncharacteristics and mechanical strength of the implant. Preferably, theapplication of the support coating 410 increases the weight of theuncoated implant 100 by about 20% to about 100% more preferably, byabout 24% to about 70%, more preferably by about 30% to about 60%, andmore preferably more than about 35%.

In yet another embodiment, the strengthening means includes theincorporation of additives into one or more of the strands. In oneexample, such additives are neutralizing agents such as calcium salts(e.g., calcium carbonate or calcium phosphate) or other salts such asbarium salts that increase the mechanical strength of the strands intowhich they are incorporated, and further act to neutralize any acidicbyproducts resulting from the degradation of the strand material(s). Inanother example, such additives are plasticizers such as polyethyleneglycol (PEG) that dissolve from the strand(s) in-vivo, thus increasingthe flexibility of the strand(s) and the implant over time.

In one embodiment, the implant 100 delivers one or more therapeuticagents at the site of implantation. The terms “therapeutic agents” and“drugs” are used herein interchangeably to mean any material that has atherapeutic effect at an implantation site. Also as used herein, thedevice of the present invention is said to “deliver” or “elute”therapeutic agent—these terms are used synonymously and generally torefer to any mechanism by which the therapeutic agent comes into contactwith tissue.

The therapeutic agent(s) may be applied to one or more strands fordelivery therefrom in a number of ways. In one example, the therapeuticagent(s) are embedded within a conformal polymer coating 210 thatadheres to one or more individual strands of the implant 100. Such acoating 210 is preferably made from a biodegradable polymer admixed withthe therapeutic agent(s) such that the agent is eluted from the polymerover time, or is released from the coating as it degrades in-vivo. Inanother example as shown in FIG. 4, one or more therapeutic agents areapplied in discrete areas 220 on one or more individual strands (shownas length of individual strand). Like coating 210, discrete areas 220are preferably made from a biodegradable polymer admixed with thetherapeutic agent(s) and eluted from the polymer over time, or arereleased from the coating as it degrades in-vivo. In either of coating210 or discrete areas 220, the biodegradable polymer may be the same asor different from the biodegradable polymer(s) used in the strands ofthe implant. In yet another example, the therapeutic agent(s) areadmixed or contained the strand(s) of the implant 100 such that theagent(s) are eluted from the one or more strands over time, or arereleased from the one or more strands as the strand(s) degrade in-vivo.In yet another example, the therapeutic agent(s) are mixed within thesupport coating 410 without any additional coating. Likewise, inembodiments in which the implant 100 is a non-woven structure, thetherapeutic agent(s) may be admixed with the polymer used to fabricatethe implant 100. Generally, the implant designs of the present inventionmay present a significantly higher surface area, with more closelyspaced strands or struts, when compared with conventional metallicstents, thus offering the possibility of a more uniform distribution ofdrug in the tissue surrounding the implant.

The therapeutic agent(s) used in the present invention are any suitableagents having desired biological effects. In a preferred embodiment, thetherapeutic agent used in the present invention is paclitaxel, itsanalogs, or derivatives thereof.

Coating 210 or areas 220 containing one or more therapeutic agents areapplied to implant 100 by any suitable method, such as spraying,electrospraying, rolling, dipping, chemical vapor deposition, andpotting. As an alternative embodiment, coating 210 or areas 220 arefurther coated with a biodegradable or biostable topcoat as shown inFIG. 5 (individual strand shown in cross-section), that acts to regulatethe deliver of the therapeutic agent from coating 210 or areas 220 intobodily tissue. In one embodiment, the topcoat 211 acts as a diffusionbarrier such that the rate of delivery of the therapeutic agent(s) arelimited by the rate of its diffusion through the topcoat 211, In anotherembodiment, the therapeutic agent(s) cannot diffuse through the topcoat211 such that delivery thereof is simply delayed until the degradationof the topcoat 211 is complete. The topcoat 211 preferably comprises abiodegradable polymer that is the same as or different from that of thecoating 210 or the strands. If implant 100 is a woven structure, coating210, 220, or 211 may be applied to individual strands prior to forminginto the woven structure, or to the woven structure after the formationthereof. If implant 100 is a non-woven structure, coating 210, 220, or211 may be applied, for example, to a solid polymer tube either beforeor after the removal of material such as by laser cutting to form apatterned, non-woven structure. In embodiment that include supportcoating 410, the coating 210, 220 and/or 211 are preferably applied oversuch support coating 410, or the support coating 410 itself may includethe therapeutic agent(s) in lieu of a separate coating 210.Alternatively, the coating 210, 220, and/or 211 may be applied betweenthe supporting coating 410 and the implant 100.

Preferred embodiments of the present invention comprise the strandslisted in Table I, with a conformal coating 210 comprising paclitaxel astherapeutic agent. The paclitaxel is preferably added to the polymermaterial that comprises the coating 210 before the coating 210 isapplied. The inventors have surprisingly found that it is possible toachieve favorable preclinical results from the use of such embodimentsin which the drug content of the coating 210 is significantly reduced incomparison to conventional drug-eluting stents. For example, for theembodiments listed in Table I, the inventors have found favorablepreclinical results with paclitaxel content specified in Table II:

TABLE II Paclitaxel content in implants of the present invention. Amountof paclitaxel (micrograms per square millimeter of implant surface area)No. of strands 0.003″ strands 0.004″ strands 0.005″ strands 0.006″strands 0.007″ strands 32 0.004-0.088 0.003-0.066 0.003-0.0530.002-0.044 0.002-0.038 24 0.005-0.117 0.004-0.088 0.003-0.0700.002-0.059 0.002-0.050 16 0.008-0.175 0.006-0.132 0.005-0.1050.004-0.088 0.004-0.075

As can be seen from inspection of Table II, embodiments of the implantsof the present invention comprise an amount of paclitaxel within therange of about 0.002-0.175 micrograms per square millimeter of implantsurface area. In certain preferred embodiments, the implants of thepresent invention comprise an amount of paclitaxel within the range ofabout 0.002-0.15, 0.002-0.125, 0.002-0.10, 0.002-0.08, 0.002-0.06,0.002-0.04, 0.002-0.02, 0.002-0.008, 0.002-0.006, and 0.002-0.004micrograms per square millimeter of implant surface area. The inventorsbelieve these loading amounts to be significantly less than know forconventional drug eluting stents.

In preferred embodiments, implants of the present invention comprisestrands as described in Table II coated with a conformal support coating410, and further coated with a coating 210 comprising paclitaxel;wherein the strands comprise PLGA 88:12 (wt:wt), the support coating 410comprises PLCL 50:50 (wt:wt) crosslinked with HDI and chain terminatedwith dodecanol, and the coating 210 comprises PLCL 70:30 (wt:wt) withpaclitaxel incorporated therein. In such preferred embodiments: thediameter of the strands is about 150 microns, woven into a single fiberover 2 under 2 regular pattern; the thickness of the support coating 410is 20-30 microns in thickness in the radial direction on individualstrands, with a preferred maximum thickness of 250 microns at the braidnodes (i.e., where the strands overlap in the braid structure); and thethickness of coating 210 is about 3 microns.

The implant 100 of the present invention is preferably self-expanding inthat it is manufactured at a first diameter, is subsequently reduced or“crimped” to a second, reduced diameter for placement within a deliverycatheter, and self-expands towards the first diameter when extruded fromthe delivery catheter at an implantation site. the first diameter ispreferably at least 10% larger than the diameter of the bodily lumeninto which it is implanted. The implant 100 is preferably designed torecover at least about 80% and up to about 100% of its manufactured,first diameter. The inventors have found that implants in accordancewith the present invention have a recovery diameter greater than 80%,and preferably greater than 90%, of the manufactured, first diameterafter being crimpled into exemplary delivery catheters of either 1.8 mmor 2.5 mm inner diameter and held for one hour at either roomtemperature (25° C.) or body temperature (37° C.).

The present invention is further described with reference to thefollowing non-limiting examples.

Example 1

Braided implants were manufactured using a PLGA 12:88 (wt:wt) copolymerby spooling fiber span monofilaments onto individual bobbins. Eachbobbin was placed on a braiding machine, strung through rollers andeyelets and wrapped around a mandrel. The braiding tension of themachine was set for the size of the monofilament (i.e., 70 g min, 215 gmax for 0.005″ fiber). The pix/inch was set to obtain an ideal angle tomaximize radial strength but still allow the braid to be removed fromthe mandrel (i.e., 110 to 135 degrees for a 6 mm mandrel). The braidpattern was selected and the monofilaments were braided off the spoolonto the mandrel by the braiding machine. Tiewraps were used on the endof each mandrel to keep the tension on the filaments, which can beimportant for heat annealing and obtaining high modulus properties. Thebraided polymer was heat annealed on the mandrel, and then cut intodesired lengths with a blade and removed from the mandrel. Arepresentative implant was measured to have an outer diameter of about6.0 mm and a length of about 20 mm.

Implants were coated with a support coating made frompoly(glycolide-co-caprolactone) (PGCL) cured with hexamethylenediisocyanate. The PGCL 50:50 (wt:wt) copolymer was prepared as follows.A 100 mL round-bottom flask was dried in oven in 110° C. and then cooledto room temperature under a nitrogen atmosphere. The flask was chargedwith Sn(Oct)₂ (15 mg), pentaerythritol (68 mg), glycolide (10.0 g), andε-caprolactone (10.0 g), respectively. Subsequently, the flask wasequipped with a magnetic stir bar and a three-way valve connected to anitrogen balloon. The flask was thoroughly degassed under reducedpressure and flushed with nitrogen. The flask was then placed into anoil bath which was preheated to 170° C. The reaction was stirred at 170°C. for 24 h under a nitrogen atmosphere. After cooling to roomtemperature, the solid obtained was dissolved in dichloromethane andprecipitated from anhydrous diethyl ether. The solution was decanted andthe residual sticky solid was washed thoroughly with diethyl ether anddried in vacuum. Typically, around 18 g of polymer was recovered throughthe purification. GPC characterization revealed a number averagemolecular weight (Mn) of 39,900 and a polydispersity index (PDI) of1.23.

The four-arm PGCL 50:50 (wt:wt) (1.0 g) and HDI (375 μL) were dissolvedin 20 mL dichloromethane to make a stock solution for spray-coating. Asteel mandrel of 2 mm in diameter was mounted vertically onto amechanical stirrer, and the braided implant was placed over the mandrel.A spray gun (Badger 150) was arranged perpendicular to the mandrel, andconnected to a nitrogen cylinder and a reservoir containing the stocksolution. The mechanical stirrer was turned on to spin the mandrel andthe solution was sprayed onto the braid by applying the nitrogen flow.The coating weight could be controlled by the spray time. After spraycoating, devices were dried in air for 1 h and then cured at 100° C. for16 h. A catalyst such as tin octanoate, zinc octanoate, aluminumtris(acetylacetonate), etc. may also be used in the curing process toreduce the curling time and/or temperature.

Example 2

Braided implants having an as-manufactured diameter of 6 mm weremanufactured using a PLGA 79:21 (wt:wt) copolymer using a manufacturingprocess similar to that of Example 1. The implants were coated with asupport coating made from PLCL 50:50 (wt:wt) prepared as follows. A 250mL round-bottom flask was dried in an oven at 110° C. and cooled to roomtemperature in a nitrogen atmosphere. The flask was charged withSn(Oct)₂ (11.5 mg), pentaerythritol (204 mg), lactide (30.0 g), andε-caprolactone (30.0 g), respectively. Subsequently, the flask wasequipped with a magnetic stir bar and a three-way valve connected to anitrogen balloon. The flask was thoroughly degassed under reducedpressure and flushed with nitrogen. The flask was then placed into anoil bath which was preheated to 170° C. The reaction was stirred at 170°C. for 48 h under a nitrogen atmosphere. After cooling to roomtemperature, the highly viscous liquid obtained was dissolved inapproximately 200 mL dichloromethane and precipitated from 1200 mLanhydrous diethyl ether. The solution was decanted and the residualsticky polymer was washed thoroughly with diethyl ether and dried undervacuum. Typically, around 48 g polymer was recovered through thepurification. GPC characterization revealed a number average molecularweight (Mn) of 52,500 and a polydispersity index (PDI) of 1.2.

Example 3

Braided implants having an as-manufactured diameter of 6 mm weremanufactured using a PLGA 79:21 (wt:wt) copolymer using a manufacturingprocess similar to that of Example 1. The implants were coated with asupport coating made from poly trimethylene carbonate (PTMC) andhexamethylenediisocyanate. The PTMC three arm polymer was prepared asfollows. A 100 mL round-bottom flask, previously dried under heat andvacuum, was charged with Sn(Oct)₂ (20 mg), triethanolamine (298.4 mg)and trimethylene carbonate (30 g) respectively. Subsequently, the flaskwas equipped with a magnetic stir bar and a three-way valve connected toa nitrogen balloon. The flask was thoroughly degassed under reducedpressure and flushed with nitrogen and then placed into an oil bathwhich was preheated to 70° C. The oil bath temperature was thenincreased to 100° C. over 15 minutes. The reaction was stirred at 100°C. for 23 k under a nitrogen atmosphere. After cooling to roomtemperature, the viscous liquid obtained was dissolved overnight inapproximately 50 mL dichloromethane and subsequently precipitated from550 mL ethanol. The precipitated polymer was stirred for one hour afterwhich the ethanol was decanted. The process of dissolving the polymer indichloromethane and precipitating in ethanol was repeated. The polymerwas then dissolved in dichloromethane, precipitated into 550 mL diethylether and stirred for one hour after which time the diethyl ether wasdecanted. The polymer was then dried under vacuum at 70° C. for a periodof 72 hours. Typically 24 g of polymer was recovered using aboveprocess. GPC characterization of the final polymer revealed a numberaverage molecular weight (Mn) of 29 kDa and a polydispersity index (PDI)of 2.0.

Example 4

A support coating solution was prepared by dissolving 1.0 g of PLCL50:50 (wt:wt) copolymer (Mn=67 kDa) in 19.875 mL of methylene chloride.Subsequently, 0.125 mL of hexamethylene diisocyanate is added to thesolution, which was then transferred to a 60 mL polypropylene syringeusing a 14 gauge needle. No catalyst was added to the support coatingsolution at any time.

The support coating solution was spraying onto PLGA 88:12 (wt:wt)braided implants. After spray coating, the implants were allowed to dryfor up to 60 minutes in a nitrogen atmosphere. The implants were thentransferred to a curing oven for a two step curing process consisting ofa first step at 75° C. for 16 hours, followed by a second step at 100 °C. for a minimum of 96 hours.

Example 5

Braided tubular implants were prepared in accordance Example 1. Theimplants each comprised 32 strands of 88:12 (wt:wt) poly(L-lactic acidco-glycolic acid) copolymer (PLGA), braided into 7 mm diameter tubes.The strands had diameters of 0.006″ and were woven in a single fiberover 2 under 2 regular pattern. The as-manufactured braided implantswere coated with a conformal support coating comprising 50:50 (wt:wt)poly(lactic acid-co-caprolactone) copolymer (PLCL) crosslinked withhexamethylene diisocyanate. The support coating was 20-30 microns inthickness in the radial direction on individual strands, with a maximumthickness of about 250 microns at the braid nodes where the strandsoverlapped. The coated implants were further coated with an additionalconformal coating comprising a mixture of PLCL 75:25 (wt:wt), andpaclitaxel as therapeutic agent.

In different samples, the amount of paclitaxel incorporated into theoutermost coating, and thus carried by 27 mm long implants, was 4, 8 and12 micrograms total or 0.003 micrograms, 0.007 microgram, and 0.010micrograms per square millimeter of implant surface area, respectively.To assess the drug elution from the implants over time, these implantsunderwent simulated deployment through a delivery catheter and placedindividually into a media of phosphate-buffered saline (PBS) at pH 7.4containing a surfactant. The implants were conditioned for 63 days at37° C. with mild agitation in order to simulate physiologic conditions.The media was analysed by HPLC at selected time points to determine theamount of paclitaxel eluting from the device coating over time. FIG. 6shows the average cumulative paclitaxel eluting from the coated devicesover time. After 7 days in release media, approximately 50% of thepaclitaxel loaded on scaffolds eluted regardless of the drug dose. Thetotal loading of paclitaxel in all scaffolds completely eluted within 42days. No paclitaxel was detected in the media for 3 consecutive timepoints between 42 through 63 days. The devices were removed from themedia at 63 days. After removal from the media, the devices were soakedin DCM to extract any residual paclitaxel. No un-released paclitaxel wasdetected on any of the devices, confirming that all paclitaxel hadcompletely eluted.

Example 6

The implants of Example 5 were evaluated for device safety and vesselpatency in sheep peripheral arteries. In different embodiments, 7×40 mmimplants containing 4, 8, and 12 micrograms of paclitaxel (or 0.002micrograms, 0.004 micrograms, and 0.007 micrograms per square millimeterof implant surface area, respectively) were implanted in the superficialfemoral arteries (SFA) of five Suffolk Cross-bred sheep (80-100 Kg inweight). The profunda arteries (PFA) of these sheep were also implanteddue to its close anatomic location with SFA. Bare implants (i.e.,without any drug coating) were also implanted as control devices. Thesheep were euthanized as planned at one month post implantation. Theassessment included:

-   -   overall safety, as determined by device related animal deaths,        adverse events (AEs), and overall animal health;    -   vessel patency, defined as <50% mean diameter stenosis from two        orthogonal angiography planes measured by quantitative vascular        angiography (QVA);    -   semi-quantitative histopathology assessments of treated vessels        for device safety and biocompatibility.

All implants were successfully deployed without incidence of vesseldissection or thrombosis. During the one month in-life period, therewere no animal deaths or AEs. The animal weight changes were asexpected. Overall animal health remained normal throughout the study.Daily gait evaluation of the implanted animals showed no sign ofabnormal gait behaviour. At necropsy, examination of all the externalsurfaces and orifices, especially the surface of the hind limbs;muscular/skeletal system; thoracic, abdominal and pelvic cavities withtheir associated organs and tissues; central nervous system (excludingbrain) from every animal showed no evidence of abnormal finding.

Vessels implanted with all implants and bare controls were widely patentby QVA at one month post implantation.

Example 7

To determine the in-vivo drug release of the implants of the presentinvention, the three formulations of Example 5 were implanted in thesuperficial femoral arteries (SFA) or profunda arteries (PFA) of SuffolkCross-bred sheep (80-100 Kg in weight). Devices were explanted at 1 day,7 days, and 30 days.

Explanted vessels containing the implants were cut into slices andplaced in vials. Paclitaxel remaining in the explanted slices wasextracted by soaking in DCM. The extracted samples were purified using amethanol precipitation and analysed using an HPLC to quantify the amountof paclitaxel remaining on each device and attached tissue. The amountof paclitaxel eluted from each device was calculated from the knowninitial paclitaxel loading and the measured amount remaining on thescaffold and attached tissue.

Although the implants containing 8 and 12 micrograms of paclitaxel wereloaded with 2 and 3 times the amount of paclitaxel as those implantscontaining 4 micrograms, the relative percentage of paclitaxel elutingover time was approximately equivalent. Approximately 50% of the loadedpaclitaxel eluted after 7 days and 98% eluted after 30 days in-vivo,independent of the initial paclitaxel load.

The elution of paclitaxel from the implants tested in-vitro is mostrapid immediately after initiation drug release testing. At relativelylonger time points, 7 and 30 days, there is good agreement between theamount of paclitaxel eluting from the scaffold in-vivo and in-vitro forall three doses. This suggests that the in-vitro release assessmentaccurately predicts the approximate amount of paclitaxel released fromthe scaffold after implantation.

Summary of Examples 6-7

In all animals treated with implants of the present invention, therewere no device related animal deaths, AEs and animal health remainednormal. All implants were deployed as expected and all treated vesselswere patent. Histology analyses of implanted vessels showed paclitaxeldose dependent tissue responses with normal tissue healing in all threepaclitaxel doses at one month post implantation. In-vivo drug releaseresults correlated well in-vitro drug release results. Plasma PKanalysis demonstrated non-detectable levels of systemic paclitaxelcontent. These animal study results support the safety and performanceof the implants.

The present invention provides woven and non-woven self-expandingmedical implants for placement within a bodily lumen that havesufficient strength and other mechanical properties that are necessaryto effectively treat a variety of medical conditions. While aspects ofthe invention have been described with reference to example embodimentsthereof, it will be understood by those skilled in the art that variouschanges in from and details may be made therein without departing fromthe scope of the invention.

1-16. (canceled)
 17. A medical implant comprising: a tubular structurecomprising struts and open spaces between adjacent said struts, whereinsaid tubular structure is biostable; a first conformal coatingcomprising paclitaxel and a first polymeric material at least partiallycoating said struts; wherein said tubular structure is characterized bya surface area of from 11.4 to 53.8 mm2/mm length of the tubularstructure, and the amount of paclitaxel is within the range of about0.002 to about 0.175 micrograms per square millimeter of said surfacearea; and wherein the paclitaxel is the sole therapeutic agent in themedical implant.
 18. The medical implant of claim 17, wherein the amountof paclitaxel is within the range of about 0.002 to about 0.09micrograms per square millimeter of said surface area.
 19. The medicalimplant of claim 17, wherein the amount of paclitaxel is within therange of about 0.003 to about 0.12 micrograms per square millimeter ofsaid surface area.
 20. The medical implant of claim 17, wherein theamount of paclitaxel is within the range of about 0.004 to about 0.175micrograms per square millimeter of said surface area.
 21. The medicalimplant of claim 17, wherein said tubular structure comprises a totalamount of paclitaxel within the range of about 0.1 to about 2.0micrograms per millimeter of length of said tubular structure.
 22. Themedical implant of claim 21, wherein said tubular structure comprises atotal amount of paclitaxel within the range of about 0.2 to about 2.0micrograms per millimeter of length of said tubular structure.
 23. Themedical implant of claim 17, further comprising a second conformalcoating at least partially coating said first conformal coating, saidsecond conformal coating comprising a second polymeric material.
 24. Themedical implant of claim 23, wherein each of the first and secondpolymeric materials is biodegradable.
 25. The medical implant of claim23, wherein said second conformal coating has a thickness up to 8microns.
 26. A medical implant comprising: a tubular structurecomprising struts and open spaces between adjacent said struts, whereinsaid tubular structure is biostable; a first conformal coatingcomprising a first polymeric material and at least partially coatingsaid struts; and a second conformal coating at least partially coatingsaid first conformal coating, said second conformal coating comprising asecond polymeric material and paclitaxel as a single therapeutic agentin said medical implant; wherein said tubular structure is characterizedby a surface area, and the amount of paclitaxel is within the range ofabout 0.002 to about 0.175 micrograms per square millimeter of saidsurface area.
 27. The medical implant of claim 26, further comprising athird conformal coating at least partially coating said second conformalcoating, said third conformal coating comprising a third polymericmaterial.
 28. The medical implant of claim 27, wherein each of thefirst, second and third polymeric materials is biodegradable.
 29. Themedical implant of claim 28 wherein said third conformal coating has athickness up to 8 microns.
 30. A medical implant comprising: a tubularstructure comprising struts and open spaces between adjacent saidstruts, wherein said tubular structure is biostable; a first conformalcoating comprising a first polymeric material and at least partiallycoating said struts; and a second conformal coating at least partiallycoating said first conformal coating, said second conformal coatingcomprising a second polymeric material and an amount of paclitaxel as asingle therapeutic agent in said medical implant; wherein said tubularstructure is characterized by a surface area, wherein the amount ofpaclitaxel is within the range of about 0.002 to about 0.175 microgramsper square millimeter of said surface area, and wherein said tubularstructure has a surface area within the range of about 11.4 to about53.8 square millimeters per millimeter length of said tubular structure.31. The medical implant of claim 30, wherein said tubular structurecomprises a total amount of paclitaxel within the range of about 0.1 toabout 2.0 micrograms per millimeter length of said tubular structure.32. The medical implant of claim 30, wherein said tubular structurecomprises a total amount of paclitaxel within the range of about 0.2 toabout 2.0 micrograms per millimeter of length of said tubular structure.33. The medical implant of claim 30, wherein the amount of paclitaxel iswithin the range of about 0.002 to about 0.02 micrograms per squaremillimeter of said surface area.
 34. The medical implant of claim 30,further comprising a third conformal coating at least partially coatingsaid second conformal coating, said third conformal coating comprising athird polymeric material.
 35. The medical implant of claim 34, whereineach of the first, second and third polymeric materials isbiodegradable.
 36. The medical implant of claim 26, wherein said tubularstructure comprises a total amount of paclitaxel within the range ofabout 0.1 to about 2.0 micrograms per millimeter length of said tubularstructure.
 37. The medical implant of claim 26, wherein said tubularstructure comprises a total amount of paclitaxel within the range ofabout 0.2 to about 2.0 micrograms per millimeter of length of saidtubular structure.
 38. The medical implant of claim 36, wherein theamount of paclitaxel is within the range of about 0.002 to about 0.02micrograms per square millimeter of said surface area.